Although simian immunodeficiency virus (SIVsmm) induces AIDS when inoculated into rhesus macaques, it does not produce immunodeficiency in its natural host, the sooty mangabey. The absence of disease in SIV-infected sooty mangabeys is not due to better control of viral replication, since naturally-infected animals have viral loads that are comparable to those detected in SIV infected rhesus macaques with AIDS. Although antigen-specific cytotoxic T lymphocytes (CTL) can protect against disease by effective control of viral replication, as is pathogenic HIV or SIV infection, they can also cause disease by inducing immunopathology, as in certain instances of lymphocytic choriomeningitis virus infection in mice. SIV-specific CTL activity of variable intensity is detected in naturally SIV- infected sooty mangabeys. However, it is not known whether it controls SIV replication in vivo, albeit ineffectively, and whether weak or ineffective immune responses are essential for maintaining apathogenic infection. We hypothesize that SIV-specific CTL in naturally SIV-infected sooty mangabeys are functionally defective in vivo. This defect is partly due to inadequate T helper function of SIV- specific CD4+ T lymphocytes. In the setting of high viral loads, an ineffective CTL response prevents immunodeficiency by reduced killing of infected CD4+ T lymphocytes, decreased T-cell mediated immunopathology and preservation of antigen presenting cells. Our Specific Aims are: 1. To investigate the relationship between SIV replication and SIV-specific cellular immune responses in sooty mangabeys naturally infected with SIV. 2. To examine if there are quantitative or functional differences between T lymphocytes targeting SIV and CMV in asymptomatic sooty mangabeys naturally-infected with SIV. 3. To investigate the kinetics and specificity of the host immune response in early SIV infection in sooty mangabeys, and to examine if CTL escape is a mechanism of viral persistence. 4. To characterize SIV-specific CTL epitopes and their restricting MHC class I alleles in sooty mangabeys in order to produce MHC class I tetramers. These studies should provide valuable information on the function of CD4+ and CD8+ T cells in SIV-infected sooty mangabeys and help to provide a comprehensive foundation on which to build future studies of lentivirus pathogenesis in this important model.